Osteoporotic bone loss from excess iron accumulation is driven by NOX4-triggered ferroptosis in osteoblasts.
Free Radic Biol Med
; 198: 123-136, 2023 03.
Article
em En
| MEDLINE
| ID: mdl-36738798
ABSTRACT
Excess iron accumulation is a risk factor for osteopenia and osteoporosis, and ferroptosis is becoming well understood as iron-dependent form of cell death resulting from lipid peroxide accumulation. However, any pathological impacts of ferroptosis on osteoporosis remain unknown. Here, we show that ferroptosis is involved in excess-iron-induced bone loss and demonstrate that osteoporotic mice and humans have elevated skeletal accumulation of the NADPH oxidase 4 (NOX4) enzyme. Mechanistically, we found that the NOX4 locus contains iron-response element-like (IRE-like) sequences that are normally bound (and repressed) by the iron regulatory protein 1 (IRP1) protein. Binding with iron induces dissociation of IRP1 from the IRE-like sequences and thereby activates NOX4 transcription. Elevated NOX4 increases lipid peroxide accumulation and causes obvious dysregulation of mitochondrial morphology and function in osteoblasts. Excitingly, the osteoporotic bone loss which we initially observed in an excessive-iron accumulating mouse line (Hepc1-/-) was blocked upon treatment with the ferroptosis-inhibitor ferrostatin-1 (Ferr-1) and with the iron chelator deferoxamine (DFO), suggesting a potential therapeutic strategy for preventing osteoporotic bone loss based on disruption of ferroptosis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoporose
/
Sobrecarga de Ferro
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Ferroptose
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article